HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo.
HER2 reduces breast cancer radiosensitivity by activating focal adhesion kinase in vitro and in vivo.
复制标题
HER2 通过激活体外和体内粘着斑激酶降低乳腺癌放射敏感性
DOI：
10.18632/oncotarget.9870
复制
发表时间：
2016-07-19
期刊：
影响因子：
--
通讯作者：
Guo X
中科院分区：
文献类型：
--
作者：
Hou J;Zhou Z;Chen X;Zhao R;Yang Z;Wei N;Ni Q;Feng Y;Yu X;Ma J;Guo X
越来越多的证据表明，人表皮生长因子受体2（HER 2）参与乳腺癌的辐射反应。然而，根本的机制仍然难以捉摸。因此，我们研究HER 2过表达是否与乳腺癌的放射敏感性相关。我们通过转导HER 2 cDNA或针对HER 2的短发夹RNA构建了HER 2表达不同的乳腺癌细胞系。然后，我们评估了辐射敏感性，并探讨了潜在的机制，通过使用细胞增殖试验，细胞粘附试验，失巢凋亡试验，集落形成试验，和蛋白质印迹分析。我们发现在乳腺癌细胞系MCF-7（低HER 2表达）和MDA-MB-231（HER 2不表达）中引入HER 2促进细胞增殖和侵袭，并增强细胞粘附和抗失巢凋亡。此外，与相应的对照组相比，HER 2降低了这两种细胞的放射敏感性。当使用HER 2 shRNA在乳腺癌细胞系ZR-7530和SK-BR-3（均具有高表达HER 2的细胞）中沉默HER 2时，观察到相反的结果。此外，动物实验结果表明，HER 2可增强异种移植瘤的放射抵抗性。进一步的研究表明，HER 2促进了黏着斑激酶（Fak）的磷酸化，从而上调了与上皮-间充质转化相关的蛋白质如Claudin-1、ZO-1和ZEB-1的表达。使用Fak抑制剂（PF-562281）抑制Fak活性可恢复HER 2过表达细胞的放射敏感性。总之，HER 2通过在体外和体内激活Fak降低乳腺癌的放射敏感性。Fak可能是HER 2过表达乳腺癌放射增敏的潜在靶点。
Growing evidence has demonstrated that human epidermal growth factor receptor 2 (HER2) is involved in the radiation response to breast cancer. However, the underlying mechanism remains elusive. Therefore, we investigated if HER2 overexpression is associated with radiosensitivity of breast cancer. We constructed breast cancer cell lines differing in HER2 expression by transducing HER2 cDNA or short hairpin RNA against HER2. We then assessed the radiosensitivity and investigated the potential mechanism by using cell proliferation assay, cell adhesion assays, anoikis assays, colony formation assays, and western blotting analyses. We found that HER2 introduction in breast cancer cell lines MCF-7 (low HER2 expression) and MDA-MB-231 (HER2 is not expressed) promoted cell proliferation and invasion and enhanced cell adhesion and resistance to anoikis. Moreover, HER2 reduced radiosensitivity in these two cells compared with the corresponding control. The opposite results were observed when HER2 was silenced in breast cancer cell lines ZR-7530 and SK-BR-3 (both cells with high expression of HER2) using HER2 shRNA. In addition, animal experiment results showed HER2 could enhance the radioresistance of xenograft tumors. Further studies showed HER2 promoted the phosphorylation of focal adhesion kinase (Fak) and thereby up-regulated the expression of proteins associated with the epithelial-to-mesenchymal transition such as Claudin-1, ZO-1, and ZEB-1. The inhibition of Fak activity using the Fak inhibitor (PF-562281) restored the radiosensitivity in HER2-overexpressing cells. In conclusion, HER2 reduces the radiosensitivity of breast cancer by activating Fak in vitro and in vivo. Fak might be a potential target for the radiosensitization of HER2-overexpressed breast cancer.
登录
查看更多内容
影响因子：
11.2
作者：
Arias-Romero LE;Villamar-Cruz O;Huang M;Hoeflich KP;Chernoff J
通讯作者：
Chernoff J
DOI：
10.1016/j.ijrobp.2004.02.018
发表时间：
2004-08-01
影响因子：
7
作者：
Buchholz, TA;Huang, EH;Sahin, AA
通讯作者：
Sahin, AA
Stanniocalicin 2 通过 PKC/claudin-1 介导的信号传导抑制乳腺癌细胞迁移和侵袭。
影响因子：
3.7
作者：
Hou J;Wang Z;Xu H;Yang L;Yu X;Yang Z;Deng Y;Meng J;Feng Y;Guo X;Yang G
通讯作者：
Yang G
乳房切除术和腋窝手术后放射疗法对10年复发和20年乳腺癌死亡率的影响：在22项随机试验中对8135名女性的单个患者数据的荟萃分析。
影响因子：
168.9
作者：
McGale, P.;Taylor, C.;Correa, C.;Cutter, D.;Duane, F.;Ewertz, M.;Gray, R.;Mannu, G.;Peto, R.;Whelan, T.;Wang, Y.;Wang, Z.;Darby, S.
通讯作者：
Darby, S.
影响因子：
11.2
作者：
Aponte M;Jiang W;Lakkis M;Li MJ;Edwards D;Albitar L;Vitonis A;Mok SC;Cramer DW;Ye B
通讯作者：
Ye B